2alpha-substituted methyl androstanes



United States Patent 3,000,912 Zen-SUBSTITUTED METHYL ANDROSTANES Lawrence H. Knox, Mexico City, Mexico, assignor to Syntex, S.A., Mexico City, Mexico, a corporation of Mexico No Drawing. Filed Jan. 4, 1961, Ser- No. 80,528 Claims priority, application Mexico Jan. 6, 1960 18 Claims. (Cl. 260-3914) The present invention relates to novel cyclopentanophenanthrene compounds and to a process for the production thereof.

More particularly the present invention relates to the dihydroallotestosterone and l9-nordihydroallotestosterone having a hydroxyrnethyl, alkoxymethyl, aralkoxymethyl or acyloxymethyl group at 0-2 and which may also contain an acyloxy group at 0-1713 and a saturated aliphatic hydrocarbon group at 0-17 or.

The novel compounds of the present invention which are valuable anabolic agents having a favourable anabolicandrogenic ratio and which show a high degree of pituitary suppression activity are represented by the following formula:

l-- g R l 0 Rune- In the above formula, R represents hydrogen or methyl; R" represents hydrogen or the acyl radical of a hydrocarbon carboxylic acid; R represents hydrogen or a lower alkyl group such as methyl, ethyl or propyl, and R represents hydrogen, a lower alkyl group, an aralkyl group containing up to 12 carbon atoms or the acyl radical of a hydrocarbon carboxylic acid.

The acyl group is derived from a hydrocarbon carboxylic acid of less than 12 carbon atoms which may be saturated, unsaturated, of straight, branched, cyclic or cyclicaliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy of up to 5 carbon atoms, acyloxy of up to 8 carbon atoms, amino, nitro, or halogen. Typical ester groups are the acetate, propionate, butyrate, caproate, enanthate, trimethylacetate, tbutylacetate, phenoxyacetate, hemisuccinate, eyclopentylpropionate, aminoacetate, benzoate and p-chloropropionate.

The novel compounds of the present invention are prepared from Z-hydroxymethylene-androstanes by the absorption of one molecular equivalent of hydrogen under controlled conditions of hydrogenation. It has not been previously possible to effect the hydrogenation of the hydroxymethylene group at C-2 with the absorption of only one molecular equivalent of hydrogen; there were always absorbed two molecular equivalents of hydrogen with the formation of the corresponding 2a-methyl compounds which are valuable hormones having a difierent effect than the novel 2-hydroxymethyl compounds.

The novel compounds of the present invention may be "ice 2 prepared by a process illustrated by the following equation:

In the above formulas R, R, R and R have the same meaning as previously described.

In practicing the process outlined above, a Z-hydroxymethylene dihydrotestosterone (I) prepared as described in US. Patent 2,908,693 and by Ringold ct aL, J. Am. Chem. Soc. 81, 427 (1959), is hydrogenated in the presence of a hydrogenation catalyst and inert solvent at a pH between 6.9 and 7.2 until one molecular equivalent of hydrogen is absorbed to form the corresponding 2a-hydroxymethyl compound (II). Suitable solvents for the hydrogenation step are lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, n-butanol, Z-butanol or a solvent such as ethyl acetate, acetone, tetrahydrofuran or other similar solvent. Hydrogenation catalysts such as palladium on carbon or palladium on barium sulfate are preferred. Variation in temperature, pressure and catalyst have a minor etfect on the course of the reaction. However, it is most critical to maintain the reaction at the designated pH range otherwise it is diflicult to stop the hydrogenation after the absorption of one equivalent of hydrogen with the result that invariably there is obtained the 2a-methyl compounds instead of the 2-hydroxymethyl compounds. An excess of hydrogen will not aifect the formation of the 2- hydroxymcthyl compounds if the pH range of 6.9 to 7.2 is maintained.

The 2-hydroxymethyl compound (II) can be esterified by conventional methods with hydrocarbon carboxylic acid anhydrides or chlorides to form monoesters (III: R =alkyl) or diesters thereof (III: R: hydrogen). By hydrogenating a 17-monoester of Z-hydroxymethylene-dihydrotestosterone or of a 17a-alkyl derivative thereof (I), there is obtained the corresponding 17-monoester of the Z-hydroxymethyl compound (II) which upon conventional esterification aifords the 2,17-diester derivative (HI). By hydrogenating a 2-hydroxymethylene dihydrotestosterone (I:R =hydrogen), there is obtained the corresponding Z-hydroxymethyl derivative (11: R =hydrogen) which upon conventional esterification results in the formation of the diester. Conventional esterification of a Z-hydroxymethyl-lh-alkyl dihydrote-stosterone results in the formation of the C-2 monoester which can be further esterified by reaction with the desired acid anhydride in benzene solution in the presence of p-toluenesulfonic acid or by heating with the desired acid anhydride in pyridine solution at 90 C. for at least 24 hours to form the 2, C-17-diester.

Alternatively, the 2-hydroxymethyl compound (II) can be etherified at -2 by reaction with an alkanol in the presence of perchloric acid or by heating with an alkyl or aralkyl halide, preferably the iodide, in a solvent such as acetone and in the presence of a base to form the compound III where R is alkyl or aralkyl.

In another aspect of the present invention the novel compounds containing an ether group at C-2 may be prepared by a process illustrated by the following equation:

In the above formulas R, R and R have the same meaning as previously described and R represents a lower alkyl or aralkyl group.

In practicing the process outlined above, a Z-hydroxymethylene dihydroallotestosterone (IV) is first etherified at 0-2 as previously described to form the 2-alkoxymethylene or Z-aralkoxymethylene derivative (V). The latter is then hydrogenated in the presence of a solvent such as methanol or ethanol and in the presence of a hydrogenation catalyst such as pre-reduced palladium on carbon or palladium on barium sulfate at room temperature and under atmospheric pressure until one molecular equivalent of hydrogen is absorbed to afford the corresponding 2a-alkoxymethyl or 2a-aralkoxymethyl compounds (VI). The hydroxy group at 0-1718 may be esterified prior to or subsequent to the hydrogenation by the conventional methods known in the art.

The following examples serve to illustrate but are not intended to limit the scope of the invention:

PREPARATION l 17-m0noacetare of 2-hydroxymethylen-androstan- 17p-ol-3-0ne 1 g. of 2-hydroxymethylenandrostan-l7fl-ol-3-one disclosed by Ringold et al., I. Am. Chem. Soc. 81, 427

(1959) was treated with 2 cc. of acetic anhydride in 10 0c. of pyridine at room temperature overnight, then it was poured into water; the precipitate was filtered, washed with water and then stirred with 50 cc. of a 5% methanolic solution of potassium hydroxide at 0 and for 5 minutes. It was immediately acidulated by addition of acetic acid, concentrated to a small volume under reduced pressure and the precipitate was filtered. There was atforded the l7-monoacetate of 2-hydroxymethylen-androstan-l7fl-ol-3-one; which was purified by recrystallization in acetone-hexane.

PREPARATION 2 According to the method described in Preparation 1, there were obtained other 17-monoesters by reaction with the respective anhydrides. Thus for example, the 17 monopropionate, the 17-monocaproate and the l7-rnono cyclopentylpropionate of 2-hydroxymethylen-androstan- 17fl-0l-3-one were obtained by using propionic acid anhydride, caproic acid anhydride and cyclopentylpropionic acid anhydride respectively. Where the acid anhydride contained more than 3 carbon atoms, the amount of the anhydride and the reaction time were doubled and the treatment with methanolic potassium hydroxide was extended until about 15 minutes.

PREPARATION 3 1 7-mon0acetate of Z-hydroxymethylene-I 7a-methylandrostan-17fl-ol-3-one 1 g. of 2 hydroxymethylene 17cc methyl-androstan- 17fl-ol-3-one [see Ringold et al., J. Am. Chem. Soc. 81, 427 (1959) was refluxed with 2 cc. of acetic anhydride in 10 cc. of pyridine for 12 hours, at the end of which time it was poured into ice water, and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, then with a 5% aqueous solution of sodium bicarbonate and finally with water to neutral, dried over anhydrous sodium sulfate and concentrated to dryness, alfording the crude diacetate of Z-hydroxy-methylene-17amethyl-androstan-l7fl-ol-3-one. The diacetate was then stirred with 50 cc. of a 1% methanolic solution of potassium hydroxide, at 5 C. for half an hour, at the end of which period it was acidulated by addition of acetic acid, concentrated to a small volume and diluted with ice water. The solid was filtered and purified by recrystallization in acetone-hexane and there was aflorded the 17-monoacetate of 2 hydroxymethylene l'la-rnethyl-androstan- 17,8-01-3-one.

PREPARATION 4 17-monoesters of the Z-hydroxymethylene-l7a-methylandrostan l7/3-0l-3-one other than the acetate were obtained by following the method described in Preparation 3, but using instead of acetic anhydride, the anhydride of another carboxylic acid of up to 12 carbon atoms. Particularly, there were prepared the 17-propionate, 17-caproate and l7-cyclopentylpropionate of Z-hydroxymethylene- 1 7a-methyl-androstan-17fl-ol-3-one.

PREPARATICN 5 l7 monoesters of 2 hydroorymethylene 17a ethylandrostan-l7fi-ol-3-one were obtained by following the methods of Preparations 3 and 4; starting from 2-hydroxymethylene-17a-ethyl-androstan-17fi-ol-3-one, there were especially prepared the 17-acetate, l7-pnopionate, 17-caproate and l'l-cyclopentylpropionate of Z-hydroxymethylene-17a-ethy1-audrostan-17p-ol-3-one.

PREPARATION 6 10 g. of 19-nor-androstan-17p-ol-3-one in mixture with ml. of benzene, 10 ml. of ethyl formate and 1.9 g. of sodium methoxide were kept for one day at room ternperature under an atmosphere of nitrogen. The precipitate was filtered, washed with benzene, then hexane and dried in vacuo. The dried powder was added in portions with stirring to a cold solution of 25 ml. of concentrated hydrochloric acid in 250 ml. of water. The mixture was stirred for 30 minutes the precipitate filtered, washed with water, dried and crystallized from ethyl acetate to give 2-hydroxymethylene-l9-nor-androstan-l7p-ol-3-one.

PREPARATION 7 By following the procedure described in Preparation 6 except that l7a-ethyl-19-nor-androstan-llfl-ol-3-one was employed as the starting material, there was finally obtained 2 hydroxymethylene-17a-ethyl-19-nor-androstan- 17fi-ol-3-one.

PREPARATION 8 By following the method disclosed by Ringold et al., I. Am. Chem. Soc. 81, 427 (1959), l7a-propyl-19-norandrostan-Ufl-ol-S-one was transformed into Z-hydroxymethylene-17e-propyl-l9-nor-androstan-l7p-ol-3-one.

PREPARATION 9 By following the procedure described in Preparations 1 and 2 except that the Z-hydroxymethylen-androstanl7fl-ol-3-one was substituted by the corresponding 19-nor compound, there was obtained the 17-mon0acetate, l7- monopropionate, l7-monocaproate and 17-monocyclopentylpropionate of Z-hydroxymethylene-19-nor-androstan-17p-ol-3-one.

PREPARATION 10 By following the methods of Preparations 3 and 4, 2- hydroxymethylene-Hot-methyl-l9-nor-androstan-l7p-ol-3- one was converted into its 17-monoacetate, l7-monopropionate, 17-monocaproate and l7-monocyclopentylpropionate.

In a similar manner there were formed the 17-mono acetate, 17-monopropionate, 17-monocaproate and 17- monocyclopentylpropionate of 2-hydroxymethy1ene-17aethyl-19-nor-androstan-17fi-ol-3-one and of Z-hydroxymethylene-17a-propyl-19-nor-androstan-1 7 p-ol-3 -one.

EXAMPLE I In 200 cc. of methanol (distilled over potassium hydroxide) containing 6 g. of pro-reduced 5% palladium on carbon, there was suspended 20 g. of Z-hydroxymethylene- 17a-methyl-androstan-17/3-01-3-one, disclosed by Ringold et al., I. Am. Chem. Soc. 81, 427 (1959). The mixture was hydrogenated under initial pressure of 30 pounds until 1 molar equivalent of hydrogen was absorbed. The catalyst was filtered, the filtrate was evaporated to dryness under reduced pressure, and the residue was purified by chromatography on neutral alumina; a small quantity of 2a,l7a-dimethyl androstan-l7fl-ol-3-one was eluted with benzene. By subsequent elution with benzene-ether (4:1) there was obtained 16.7 g. of 2a-hydroxymethyl-1'7amethyl-androstan-l7fl-ol-3-one; M.P. 205206 C., [m1 +20 (chloroform).

EXAMPLE II By following the procedure described in the foregoing example, there was obtained from Z-hydroxymethylcnandrostan-17fl-ol-3-one [disclosed by Ringold et al., I. Am. Chem. Soc. 81, 427 (1959)] the novel Za-hYdIOXY- methyl-androstan-17B-ol-3-one; M.P. 190-192"; [e1 +36 (chloroform).

EXAMPLE III By substituting in Example 1 the 2-hydroxymethylenandrostan-l7p-ol-3-one by the l9-nor derivative, there was obtained 2:: hydroxymethyl-l9-nor-androstan-l75-01-3- one.

In a similar manner from z-hydroxymethylene-t'le- 6 methyl-l9-nor-androstan-l7p-ol-3-one, disclosed by Ringold at al., J. Am. Chem. Soc. 81, 427 (1959) there was obtained 2a-hydroxymethyl-l7a-methy1-19-nor-androstan- 17p-ol-3-one.

EXAMPLE IV 1 g. of Za-hydroxymethyl-l7e-methyl-androstan-l7p-ol- 3-one, prepared according to Example I, was treated with 1 cc. of acetic anhydride in 5 cc. of pyridine at room temperature, and allowed to remain overnight. The mixture was poured into water, heated for half an hour on the steam bath and cooled; the precipitate was filtered, washed with water, dried and recrystallized in acetone-hexane. Thus there was obtained 2a-acetoxy-methyl-flat-methylandrostan-l7fl-ol-3-one, M.P. l2913l C.

By substituting the 2a-hydroxymethyl-17e-methyl-androstan-17p-ol-3-one by Za-hydroxymethyl-17m-methyll9-nor-androstan-l7fl-ol-3-one, there was obtained 2aacetoxymethy1-17a-methyl-19-nor-androstan 17p 01-3- one.

EXAMPLE V l g. of Za-hydroxymethyI-andmstan-l7fi-ol-3-one was treated according to the method described in Example IV, but using 2 cc. of acetic anhydride to produce finally 2u-acetoxymethy1-1718-acetoxy-androstan-B-one.

In a similar manner, 2a-hydroxymethyl-l9-nor-androstan-17fl-ol-3-one was converted into Zea-ECCIOXYDJBthyl-l7fl-acetoxy-19-nor-androstan-3-one.

EXAMPLE VI By following the methods of Examples IV and V there were treated Za-hydroXymethyl-I7a-methyl-androstan- 17p-ol-3-one and 2a-hydroxymethyl-androstan-17fi-ol-3- one, respectively, with the anhydrides of propionic, caproic and cyclopentylpropionic acids; however, the quantity of the two latter anhydrides was doubled. Thus there were finally obtained the monopropionates, monocapmates and monocyclopentylpropionates of lat-hydroxymethyl-l7a-methyl-androstan-17,6-ol-3-oue as well as the dipropionates, dicaproates and dicyclopentylpropionates of the Za-hydroxymethyl-androstan-17fi-ol-3-one.

EXAMPLE VII 1 g. of Za-hydroXymethyl-I7a-methyl-androstan-l7fiol-3-one was heated with 5 cc. of acetic anhydride in 20 cc. of pyridine at C. and for 24 hours, at the end of which time it was poured into water, heated for half an hour on the steam bath, and cooled; the precipitate was filtered, washed with water, dried and recrystallized from acetone-hexane to afford the diacetate of Za-hydroxymethyl 17a-methyl-androstan-17,8-ol-3-one, i.e. 2c: acetoxymethyl-17,8-acetoxy-17a-methyl-androstan-3-one.

EXAMPLE VIII According to the method of Example VII, there were used, instead of acetic anhydride, the anhydrides of propionic, caproic and cyclopentylpropionic acids; however, the quantity of the latter two acid anhydrides was doubled and the time of esterification increased to approximately 48 hours. Thus there were obtained the dipropionates, dicaproates and dicyclopentylpropionates, respectively, of 2a-hydroxymethyl-l 7a-methylandrostanl 7fl-ol-3-on e.

EXAMPLE Ix By following the methods of Examples VII and VIII, starting from the 2a-acyloxymethyl-17a-methylandrostan- 17B-ol-3-ones of Examples IV and VI and using for the esterification at 0-17 the anhydride of an acid different from the acid formed by the 2a-acyloxymethyl group, there were obtained the following diesters of 2a-hydroxymethyl-l7u-methyl-androstan-l7p-ol-3-one; the 2m acetoxymethyl-l7a-methyl-17fl-propionoxy androstan-3-one, the 20; acetoxymethyll7a-methyl-l7fl-capronoxy-androstan-3-one, the 20: acetoxymethyl-17a-methyl-l7p-cyclopentylpropionoxy-androstan 3 one, the Zen-propionoxy gon ola 7 methyl-lh-methyl-l7B-acetoxy-androstan-3bne, Za-propionoxymethyl-lh-methyl-l7p-capronoxy androstan-3- one, 2m-propionoxymethyl 17 a methyl-17fl-cyclopentylpropionoxy-androstan 3 one, 2a-capronoxymethyl-17amethyl-17fl-acetoxy-androstan-3-one, Za-capronoxymethyl-l7a-methyl-l7fl-propionoxyandrostan-3-one, Zm-capronoxyrnethyl 17a methyl 17B cyclopentylpropionoxyandrostan-3-one, the 2a-cyclopentylpropionoxymethyl- 17a-methyl-17B-aeetoxy-androstan-3-oue, 2a-cyclopcntylpropionoxymethyl 17o: methyl-17/8-propionoxy-androstan 3 one and 2a-cyclopentylpropionoxymethyl-17amethyl-17fl-capronoxy-androstan-3-one.

EXAMPLE X The 2a-acetoxymethyl-17p-acetoxy, 2m-acetoxymethyll7fl propionoxy, 2wacetoxymethyl-17fl-capronoxy and 2aacetoxymethyl-17 B-cyclopentylpropionoxy derivatives of 17u-methyl-androstan-3-0ne, prepared according to Examples VII and IX, were treated with a methanolic solution of potassium hydroxide to hydrolyze selectively the ester group formed with the hydroxymethyl group. Preferentially, thus 1 g. of the diester was treated with 50 cc. of 1% methanolic solution of potassium hydroxide at room temperature for 4 hours, then neutralized by addition of acetic acid, concentrated to a small volume at reduced pressure, and diluted with water; the precipitate was filtered, washed with water, dried and recrystallized from acetone-hexane. There were thus obtained the 17- acetate, 17-propionate, 17-caproate and 17-cyclopentylpropionate of 2a hydroxymethyl-l7a-methylandrostanl7fi-ol-3-one.

EXAMPLE XI The methods described in Examples I, IV, VI, VII, VIII, IX and X were applied to the corresponding starting compounds which had at -1711, instead of a methyl group, an ethyl group and there was produced the corresponding final products having the ethyl group at C-17oz.

EXAMPLE XII By following the method described in Example I, the Lhydroxymethylene-derivatives of the following compounds were hydrogenated: 17-acetate, l7-propionate, 17- caproate and 17-cyc1opentylpropionate of androstan-17fiol-3-one, 17a methyl androstan-l713-ol-3-one and 17aethyl-androstan-l7B-ol-3-one. Thus there were obtained the 2a-hydroxymethyl derivatives of the foregoing compounds with the respective ester group at 0-1718.

EXAMPLE XIII By following the method described in Example VI, Zuzhydroxymethyl-lh-methyl 19 nor-androstan-flfl-ol- 3-one and 2a-hydroxymethyl-l9-nor-androstan-175-01-3- one were converted into the propionate, caproate and cyclopentylpropionate of Za-hydroxymethyl-Not-methyl-19- nor-androstan-l7fl-ol-3-one as well as the dipropionate, dicaproate and dicyclopentylpropionate of Za-hYdrOXY- methyll9-nor-androstan- 17 5-01-3 -one.

EXAMPLE XIV By following the methods described in Examples VII and VIII, 2u-hydroxymethy1- 17a methyl-19-nor-androstan-17B-ol-3one was converted into Za-acetoXymethyI- 17p acetoxy-l7a-methyl-19-nor-androstan-3-one, Zen-PTO- pionoxymethyl 175 propionoxy-lh-methyl-l9-nor-androstan-Zi-one, 2a capronoxymethyl-l7fl-capronoxy-17umethyl-l9-nor-androstan-3-one and Za-cyclopentylpropionoxy 173 cyclopentylpropionoxy-Not-methyl-19-norandrostan-3-one identical with the compounds obtained in Example XIII.

EXAMPLE xv By following the methods of Example IX, starting from the 2a-acyloxymethyl-17a-methyl-19-nor-androstanl7fi-ol-3-ones of Examples IV and XIII, there were obtained 2a acetoxymethyl 17a-methyl-17B-propionoxy-19- nor-androstan-S-one, 2a acetoxymethyl-lh-methyh1718- capronoxy-19-nor-androstan-3 -one, 2u-acetoxymethyh 17amethyl 17p cyclopentylpropionoxy-l9-nor-androstan-3- one, 2a pro-pionoxymethyl-17u-methyl-17fi-acetoxy-1'9- nonandrostan-Zi-one, 2a propionoxymethyl-17a-methylcapronoxy-l9-nor-androstan-3-one, Za-PIOPIOHOXY- methyl 17w methyl-17fl-cyclopentylpropionoxy-l9-norandrostan-3-one, 2oz capronoxymethyl-l7a-methyl-l7fl acetoxy 19 nor-androstan-B-one, 2a-capronoxymethyl- 17 a methyl-17fl-propionoxy-l 9-nor-androstan-3-one, 2acapronoxymethyl 17a methyl-l7;3-cyclopentylpropionoxy-l9-nor-androstan-3-one, 20c cyclopentylpropionoxymethyl 17a methyl 17;? acetoxy-l9-nor-androstan-3- one, 20: cyclopentylpropionoxymethyl-17a-methyl-l7fipropionoxy-l9-nor-androstan-3-one and Za-cyclopentylpropionoxymethyl 17m methyl-17B-capronoxy-l9-norandrostan-3-one.

EXAMPLE XVI By following the procedure described in Example X, the Za-acetoxymethyl-l7B-acetoxy-l7a-methyl-l9-nor-androstan 3 one; 20: acetoxymethyl 17B propionoxy- 17a methyl l9 nor androstan 3 one; 2:: acetoxymethyl 17B capronoxy 17m methyl 19 nor -androstan-3-one and Za-acetoxymethyl-17B-cyclopentylpropionoxy 17m methyl 19 nor androstan 3 one were selectively hydrolyzed at (3-2 to form the corresponding 2a hydroxymethyl 1713 acyloxy 17oz methyl-l9-nor-androstan-3-ones.

EXAMPLE! XVII The methods of Examples I, IV, VI, VII, VIII, IX, and X were applied to the corresponding starting 19-no-randrostan-B-ones having an ethyl or a propyl group at 0-170; and there were produced the corresponding final products having an ethyl or propyl group at C-l7a.

EXAMPLE XVIII By following the method described in Example I, the 2-hydroxymethylene derivatives of the following compounds were hydrogenated: 17-acetate, 17-propionate, l7-capro-ate and l7-cyclopentylpropionate of 19-nor-androstan-17B-ol-3-one, of 17-methyl-l9-nor-androstan-17B- ol-3-one, of 17a-ethy1-19-nor-androstan-l7fl-ol-3-one, and of 17a-propyl-19-nor-androstan-17B-0l-3-one. Thus there were obtained the Za-hydroxymethyl derivatives of the foregoing compounds with the respective ester groups at 0-175.

EXAMPLE XIX 10. g. of Zhydroxymethylen-androstan-l7fi-ol-3-one was suspended in 100 ml. of methanol and 2 drops of 70% perchloric acid were added at 20 C., and the mixture was stirred at this temperature, whereby rapid dissolution of the starting steroid, followed by precipitation of the etherified compound was noted. The mixture was then left for 5 minutes at 20, subsequently chilled to 0 and the solid collected by filtration, washed with water, dried and purified by crystallization from acetonehexane. Thus, 8.3 g. of 2-methoxymethylen-androstan- 17,6-ol-3-one [M.P.] 199-200 C., [11] +1535 (chloroform), A 278 in, log e 4.00], were obtained.

5 g. of Z-methoxymethylen-androstan-17(3-ol-3-one dissolved in 200 cc. of methanol (distilled over potassium hydroxide) containing 500 mg. of a pro-reduced 5% palladium on carbon catalyst were hydrogenated at room temperature and under atmospheric pressure; after uptake of 1 molecular equivalent of hydrogen the reaction came practically to a standstill. The catalyst was separated by filtration and the filtrate evaporated to dryness under reduced pressure. The residue crystallized from acetone, yielding 4 g. of 2a-methoxymethyl-androstanl7fl-ol-3-one, MP. 18l C., [ah +30 (chloroform).

EXAMPLE xx 5 g. of z-hydroxymethylene-19-nor-androstan-17p-ol- 3-one was transformed to Z-methoxymethylene-l9-norandrostan-17B-ol-3-one and this, in its turn, hydrogenated, following the-technique described in Example XIX. Thus,

9 2a methoxymethyl 19 nor -androstan 17p ol 3- one was obtained.

EXAMPLE xx! A mixture of 2 g. of Z-hydroxymethylene-lhmethylandrostan-l7p-ol-3-one, 100 ml. of absolute methyl iodide, 100 ml. of anhydrous acetone and 2 g. of anhydrous powdered potassium carbonate was refluxed for 48 hours and then poured into water. The product was extracted with ether, the ether extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by chromatography on washed alumina giving Z-methoxymethylene-flat-methylandrostan-17B-ol-3-one. Alternatively, the 2-methoxy derivative was prepared by treatment of the hydroxymethylene compound with methanol-perchloric acid as desribed in Example XIX.

l g. of the foregoing compound was hydrogenated in accordance to the method described in Example XIX, yielding Za-methoxymethyI-l7c-methyl-androstan-l7p-ol- 3-one.

EXAMPLE XXII 2 hydroxymethylene 17a methyl l9 nor androstan-17p-ol-3-one was converted to Z-methoxymethylene 17oz methyl l9 nor -androstan 17,9 ol 3- one in accordance with the method of Example XIX and alternatively in accordance with the method of Example XXI. Hydrogenation over a palladium on carbon catalyst as in Example XIX converted Z-methoxymethylene- 17a methyl 19 nor -androstan 1713 ol 3 one to 20: methoxymethyl 17cc methyl l9 nor -androstanl7B-ol-3-one.

EXAMPLE XXIII 10 g. of Z-hydroxymethylen-androstan-l7fi-ol-3-one were suspended in 100 ml. of ethanol and 2 drops of 70% perchloric acid were added at 20 C.; the mixture was stirred at this temperature, whereby rapidly dissolution of the starting steroid, followed by precipitation of the etherified compound was noted. The mixture was then left for 10 minutes at 20 C., subsequently chilled to C. and the solid collected by filtration, water-washed, dried and purified by crystallization from acetone-hexane. Thus, 2 ethoxymethylen androstan 17,8 ol 3- one was obtained. This compound, in its turn, was bydrogenated, exactly as described for the hydrogenation of 2-methoxymethylene-androstan-l7fi-ol-3-one (Example XIX) and Za-ethOXymethyI-androstan-17B-ol-3-one was obtained.

EXAMPLE XXIV Exactly as described in Example XXIII, Z-hydroxymethylene-l9nor-androstan-l7fl ol-3-one was etherified by reaction with ethanol in the presence of perchloric acid and the resulting Z-ethoxymcthylene-l9-nor-androstanl7B-ol-3-one was hydrogenated, thus furnishing finally 2m ethoxymethyl l9 nor -androstan 17B o1 3- one.

EXAMPLE XXV By starting with the Z-hydroxymethylene-derivatives of dihydroallotestosterone, 19 nor dihydroallotestosterone and 17a-alkyl substituted derivatives thereof listed under A, the etherification procedures described in Examples XIX, XXI and XXIII were repeated, except that ethyl iodide, propyl iodide or benzyl iodide, respectively, were employed instead of methyl iodide. Thus by the use of ethyl iodide, the corresponding Z-ethoxymethylene-compounds, by applying propyl iodide, the respective 2-propoxymethylene compounds, and using benzyl iodide the respective Z-benzyloxymethylene compounds were obtained, as intermediates.

The etherified Z-hydroxymethylene compounds were hydrogenated, exactly as reported in Example XIX, and thus the desired final etherified ze-hydroxymethyl compounds, listed under 0 were produced.

Starting Compound Intermediate Ether Final Compound 2 hydroxymethylen ethyl etherificatlon 2a-ethoxymethyh androstan-17fiol-8- procedure of Examandrostan-17fi-o1-3- one. 810 one.

fl-hydroxymethylene et yl (etheriflcatlon Za-etho methyl-17al'ia-rnethyl-audroprocedure of Exammethy -androstansten-17fi-ol-3-one ples XXIII and 17tI-o1-3-one.

Example XXI). XXI).

2- ydroxymethylenpropyl (etherificatlon Za-propoxymethylandrostaml'ifl-ol-fiprocedure of Exemandr0stan-17B-ol-3- one (Example ple XXI). one.

2-hydroxymethylenemethyl (etheriflcation Za-methoxymethyi- IIaethyl-androstanprocedures of Exam- 17a-ethyl-androstan- 178-o1-3-one (U. S. ples XIX and XXI). 17B-ol-3-one.

Patent 2,908 693).

2hydroxymethylenebenzyl (etheriflcation 2a-benzyloxymethyl- 19-nor-androstanprocedure of Exem- 19-n0r-androstau- I7B-0l-3-one ple XXI). l7fi-ol-3-one. (Example XX).

Zhydroxymethylenemethyl (etherification 2a-methoxymethyl- I7a-ethyl-I9-norprocedure of Exam- 17a-ethyl-19-norandrostan-l7fl-ol-3- ples XIX and androstan-17fl-ol-3- one (Preparation 7). XXI). one.

2hydroxymethy1eneethyl (procedure of 2a'ethoxymethyl-17w ITa-propyl-lQ-nor- Example XXI). propyl-lQ-nor-androandrostan-17fl-ol-3- stan-17fi-ol-3-one. one.

2- hydroxyrnethylen benzyl (procedure of Za-benzyloxyrnethylandrostan-li'fl ol-d Example XX androstan-l7fl-ol-3- one. one.

2-hydroxyrnethylendo 2a-benzylo methyl- 17a-propy1-andro- 17a-propy -andro stan-l7fi-ol-3-one stan-17B-ol-3-one. (U.S. Patent 2,908,693).

EXAMPLE XXVI EXAMPLE XXVII l g. of Z-methoxymethylen-androstan-l7fl-ol-3-one, as prepared by the procedure of Example XIX was treated with 1 ml. of acetic anhydride in 5 ml. of pyridine at room temperature and overnight, poured into water, the product extracted with ether, the extract washed consecutively with diluted hydrochloric acid, water, aqueous sodium bicarbonate and water, and the ether evaporated. The residue was crystallized from acetone-hexane to give 2 methoxymethylen 1718 acetoxyandrostan-S-one. By subsequent hydrogenation, in accordance to Example XIX, the l7-acetate of Za-methQxymethyl-androstan-17pol-3-one was obtained. The same product was produced by direct acetylation of Za-methoxymethy-andmstan-17B- ol-3-one, prepared in accordance to Example XIX.

EXAMPLE XXVIII 1 g. of Z-benzyloxyrnethylene-androstan-17fl-ol-3-one (compare Example XXV) was treated with 2 ml. of propionic anhydride in 5 m1. of pyridine, at room temperature overnight. The mixture was poured into Water, heated on the steam bath for 1 hour, chilled and etherextracted. The product was then worked up as described in Example XXVII. Thus Z-benzyloxymethylene-androstan-17fl-ol-3-one-propionate was obtained. Subsequent hydrogenation elfected exactly as described in Example XIX, yielded 2e-benzyloxymethyl-androstan-l7fl-ol-3-one propionate. The same produce was obtained by a similar treatment of 2e-benzyloxymethyl-androstan-1718-01-3- one (Example XXV) with propionic anhydride.

EXAMPLE xxIx Exactly as described in Example XXVII, the 1718-11)- droxyl group of 2-methoxymethylene-19-nor-androstan- 17B-ol-3-one (Example XX) was reacted with acetic anhydride to yield Z-methoxymethylene-l9-nor-androstanl7fl-ol-3-one acetate, and this compound, in its turn, was hydrogenated to furnish 2a-methoxymethyl l9 nor-androstan-l7fi-ol-3-one acetate. Furthermore, also in accordance with the procedure reported in Example XXVII, 2a-methoxymethyl-l9-nor-androstan-17B-ol-3-one (Example XX) was acetylated to give 2u-methoxymethyl-19-norandrostan-l7fi-ol-3-one acetate.

I claim:

1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl radical of less than 12 carbon atoms; R is selected from the group consisting of hydrogen and a lower alkyl radical; and R is selected from the group consisting of hydrogen, lower alkyl, monocyclic aralkyl containing up to 12 carbon atoms and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

2. 2oz hydroxymethyl 17a-methyl-androstan-175-01-3- one.

3. 2a-methoxymethyl-androstan-17B-ol-3-one.

4. Za-methoxymethyl-19-nor-androstan-17l3-ol-3-one.

5. 2m acetoxymethyl 17 m-n'iethyl-androstan-17 3-ol-3 one.

6. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 2a-hydroxymethyl-androstan-l7t3-ol- 3-one.

7. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of Zea-lower alkoxymethyl-androstan- 17B-ol-3-one.

8. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of Za-monocyclic aralkoxymethylandrostan-17fi-ol-3-one.

9. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 2a-hydroxymethyl-l7a-lower alkylandrostan-17p-ol-3-one.

10. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of Zea-lower alkoxymethyl-lh-lower alkyl-androstan- 17,8-01-3 -one.

11. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of Za-monocyclic aralkoxymethyl-lhlower alkyl-androstan-l7fi-ol-3-one.

12. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 2a-hydroxymethyl-l9-norandrostan-Up-ol-B-one.

13. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 2a-lower a1koxymethyl-19-norandrostan-l -01-3 -one.

14. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 2|x-monocyclic aralkoxymethyl-19- nor-androstan-17p-ol-3-one.

15. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 2a-hydroxymethyl-17a-lower alkyl-l9-nor-androstan-l7fi-ol-3-one.

16. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 2m-lower alkoxymethyl-lh-lower alkyl-19-nor-androstan-17p-ol-3-one.

17. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of Za-monoeyclic aralkoxymethyll7a-lower alkyl-l9-nor-androstan-17;8-ol-3-one.

18. In the process of producing a compound of the following formula:

0R i IHMR,

H HO-- wherein R, R and R have the same definition as above in an inert solvent at a pH of 6.9 to 7.2.

No references cited. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 